Myocardial perfusion imaging with radionuclides is an integral component of the clinical evaluation of patients with known or suspected coronary artery disease (CAD) in current clinical practice. 99mTc has been the isotope of choice for the development of myocardial perfusion imaging agents because of its ideal nuclear properties (half-life and gamma-energy) and its diverse coordination chemistry. The use of 99mTc allows simultaneous assessment of myocardial perfusion and cardiac function in a single study. Since early 1980s, extensive research efforts have been directed towards the development of lipophilic Tc complex cations as heart imaging agent. As a result of these efforts, 99mTc-sestamibi and 99mTc-Tetrofosmin have been approved as commercial products for myocardial imaging. Despite their widespread use in clinic, they do not meet the requirements of an ideal perfusion agent at least partially due to their low first-pass extraction and high background activity in liver and lungs. Thus, there is a continuing need for better 99mTc radiopharmaceuticals for myocardial perfusion imaging. This project provides novel crown ether-containing cationic 99mTc-nitrido complex radiopharmaceuticals useful for heart imaging. The new radiopharmaceuticals that will be prepared and evaluated in the present project are based upon very promising results from our preliminary studies. These new cationic 99mTc-nitrido complexes are composed of a [99TcN]2+ core, a crown ether-containing dithiocarbamate (crowned DTC) and a triphosphine coligand. This project will use the cationic character for initial heart uptake of the cationic 99mTc-nitrido complex. Once the complex is able to enter the cell, the crown ether group may interact with intracellular K+ and form highly charged 99mTc species, which are not able to easily move out of the cell. The unique combination of cationic character with the presence of crown ether groups may result in cationic 99mTc-nitrido complexes that are substantially better than 99mTc-Sestamibi and 99mTc-Tetrofosmin. The goal of this research is to provide the proof-of-principle for the proposed cationic 99mTc-nitrido complexes. Accordingly, the SPECIFIC AIMS are: 1. Synthesis and characterization of cationic 99mTc-nitrido complexes. 2. Biological evaluation of cationic 99mTc-nitrido complexes in Sprague-Dawley rats. 3. Biological evaluation of selected cationic 99mTc-nitrido complexes in male Harley guinea pigs. 4. Structural characterization of cationic Re-nitrido complexes. If they show high heart uptake and favorable kinetics in both rat and guinea pig models, they would more likely to have a high heart uptake in humans. Once the basic principle is established, we will conduct more extensive SAR studies to explore the effect of alkoxyalkyl substituents of the triphosphine coliaands on biological properties (heart uptake and excretion kinetics) in the future. Our long-term goal is to develop new Tc complex radiopharmaceuticals for myocardial perfusion imaging. Successful development of new 99mTc perfusion imaging agents will have a profound impact on diagnostic evaluation, risk stratification, and therapeutic decision-making in patients with CAD.